Strategies for Peptide Synthesis: An Overview

[Pages:43]Strategies for Peptide Synthesis: An Overview

R OH

H2N O

O

H2N

OH

R'

Peptide Coupling Reagent

-H2O

R

O

H

N

H2N

OH

O R'

Han, S., Kim, Y. Tetrahedron, 2004, 60, 2447-2467 Albericio, F. Current Opinion in Chemical Biology, 2004, 8, 211-221 Humphrey, J., Chamberlin, R. Chem. Rev., 1997, 97, 2243-2266

Outline

1) Introduction - General Strategy

2) Coupling reagents - Carbodiimides - Uronium Reagents - Phosphonium Reagents - Organophosphorous Reagents - Acid Halogenating reagents - Racemization Pathways - Racemization Suppressants

3) Difficult Couplings - ,-disubstituted Amino Acids - Peptide Macrocylizations - N-methyl Amino Acids - Segment Condensations

4) Applications - Process Scale Solid Phase Peptide Synthesis

Introduction

- Amide Bonds are Ubiquitous in Nature - A large number of Natural products are based upon a peptide framework and exhibit a spectrum of biological activity - Currently there are many peptide therapeutics in development - The current pursuit of non-natural amino acid mimics makes coupling chemistry paramount for drug discovery and scientific advancement -There is no single strategy for amide bond formation that is a magic bullet -Advances in coupling chemistry have made formation of the most difficult amide bonds possible

General Strategy For Peptide Bond Formation

R OH

R'HN O

Peptide Bond Forming Reagent

R'''

OR'' H2N

R

O

X R'HN

O

X = Activating Group

R

O

H

N

R'HN

OR''

O R'''

Carbodiimides: Representative Examples/ Comparisons

H3C N

H3C

EDC

$2.25/gram

NCN CH3

Water Soluble by-product is easily removed in aqueous

work-up

$0.25/gram

NCN

DCC

H3C $0.90/gram

H3C NCN

DIC

CH3 CH3

Urea formed is partially soluble in many solvents and hard to purify via column chromatography

Urea formed is soluble in most organics. This is advantageous in solid phase synthesis.

CH3

H3C

CH3

NCN

CH3

BEC

NCN

CH3

CIC H3C

H3C NCN

CH3 CH3

NCN

CH3

BMC

H3C

CH3 O

O

N,N-dicyclopentylcarbodiimide

NCN

BDDC

H3C O

CH3

O

Carbodiimides: Basic Structure and Mechanism

R +HN C N

R OO

BocHN

R

HN

R

N

OO

O

RN H

NR H

BocHN

BocHN

X

X= Activator

O

X R

H2N

BocHN

O R

N H

Product

N-acyl Urea Formation

RHN

O O

NN H

N

RHN

OO NN H

Byproduct

N

Common Activators: Accelerate Reaction and Suppress Byproduct Formation

O

H3C N CH3

N OH

O

HOSu

OH

N

N

N N

HOAt

N

DMAP

O

N OH

O

N, hydroxyphthalimide

OH

N N

N

HOBt

F

F

F

F

OH

F

PfpOH

Lou Carpino: Peptide Giant UMass, Amherst

- Developed benzotriazole based aminium reagent, HATU, and elucidated the active form of the coupling agent - Introduced HOAt as an efficient additive for coupling reactions -Introduced the widely used Fmoc protecting group -Pioneered the use of amino acid fluorides as coupling agents

Uronium reagents: Basic Structure and Reactive Species

HBTU

H3C N CH3

CH3

O

N

N

CH3

N

N

Uronium

O

N N

N

H3C N

N CH3

CH3 CH3

Guanidinium

- Originally the uronium isomer was thought to be the active species

-Upon solving of the x-ray crystal structure, it was found that the guanidinium species was predominate

-However, the uronium could be prepared and was found to be more reactive than the guanidinium salt

- Original attempts to classify the reactive species were misguided based on known thermodynamic stabilities

-The two forms are readily distinguished by a shift in the IR absorption from ~1710 cm-1 (Uronium) to ~1670 cm-1 (guanidinium)

J. Org. Chem. 2001, 66, 5245-5247 Angew. Chem. Int. Ed. 2002, 41, 442

 ................
................

In order to avoid copyright disputes, this page is only a partial summary.

Google Online Preview   Download